Characterization of an antibiotic impregnated delivery system as an intracanal medicament in endodontic therapy

ABSTRACT

Endodontic fibers comprising a biocompatible polymer vehicle permeable to medicaments, or combinations of medicaments are described. Such fibers can be used, for example, in a method for the local delivery and sustained release of medicaments to periodontal or intracanal treatment sites. Endodontic fibers described include modified periodontal fibers and intracanal fibers.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent application09/963,880, filed Sep. 26, 2001, which claims the benefit of U.S.Provisional Application No. 60/240,004, filed Oct. 12, 2000, and is acontinuation-in-part of U.S. patent application Ser. No. 09/540,088,filed Mar. 31, 2000, which claims the benefit of U.S. ProvisionalApplication No. 60/127,497, filed Apr. 2, 1999. This application alsoclaims priority to Canadian Patent Application No. 2343471, filed Mar.30, 2001. The entire teachings of the above-referenced applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Endodontics is a field of dentistry concerned with the biologyand pathology of the dental pulp and periapical tissues. Endodontictreatment employs a set of techniques, such as chemomechanicaldebridement, irrigation, drainage of hard and soft tissue, trephination,and antimicrobial therapy, with the goal of avoiding the extraction of adamaged, infected or diseased tooth.

[0003] Normal vital pulp is sterile, and the role of bacterial infectionin the pathogenesis of pulpal and periapical disease is wellestablished. Infected or necrotic pulpal tissue renders the pulp chamberand root canal a potential reservoir of bacteria, and disinfection ofthe tooth is one of the primary justifications for the chemomechanicalaspects of root canal therapy. Recent data demonstrate a high incidenceof root canal failure in necrotic teeth treated in a single visit,attributed to bacteria remaining in complex anatomical spaces such asaccessory canals, fins, deltas and isthmuses (Sjorgen et al., Int. Endo.J., 30:297-306 (1997)). Other studies have reported the ability ofbacteria to migrate into dentinal tubules and survive therein (Nagaokaet al., J. Endodon., 21:70-73 (1995)). It is speculated that the successrate of endodontic treatment could be 26% higher if the root canal issuccessfully disinfected prior to the final restoration (Sjorgen et al.,Int. Endo. J., 30:297-306 (1997)).

[0004] Root canal infections are characterized as polymicrobialinfections which tend to 10 be dominated by anaerobic bacteria. As agroup, the common endodontic microbes associated with treatment failureinclude F. nucleatum, P. intermedia, P. micros, S. intermedius, P.endodontlis, P. gingivalis, P. melaninogenica, E. lentum, V. parvula, S.sanguis, P. buccae, P. oralis, and P. acnes. (Haapasalo, FEMS Immunol.and Medical Micro. 6:213-217 (1993) and Sundqvist, J. Endodon.,7:257-262 (1992)).

[0005] Post-operative periapical pain and interappointment flare-ups arealso routinely attributed to the presence of bacteria, and/or theirby-products, within the root canal. Typically, an initial bacterialinfection triggers a host-mediated inflammatory response, theconsequences of which underlie the flare-up patient's clinical symptoms.It has been reported that bacteria surviving instrumentation andirrigation proliferate rapidly in empty root canals (Bystrom andSundqvist, Oral. Surg. Oral. Med. Oral Pathol., 55:307-3 12 (1983)), andthere is a positive correlation between the number of bacteria presentin a root canal and the incidence of inter-appointment flare-ups. Thepresence of black-pigmented, gram negative anaerobes in the root canalusually accompanies patient complaints of pain, swelling, and tendernessto percussion (Haapasalo, FEMS Immunol. and Medical Micro., 6:213-217(1993)). Thus, the successful elimination of bacteria from root canalsmay lower the incidence of flare-ups.

[0006] Antibiotics have historically been used as an adjunct toendodontic treatment either by systemic or local administration.Currently, antibiotic treatment for root canal infections andexacerbations is limited to systemic administration. Thus, in light ofthe established correlations between the primary and secondary effectsof bacterial presence and the incidence of both interappointmentflare-ups and treatment failure, there is a clear need for anefficacious method of delivering and sustaining substantialconcentrations of intracanal medicaments, particularly antibiotics.

[0007] During the 1950's a polyantibiotic paste (PBSC) was devised foruse as an intracanal medicament (Grossman, L. I., .J. Amer. Dent.Assoc., 43:265-278 (1951)). PBSC consisted of penicillin to target grampositive organisms, bacitracin for penicillin-resistant strains,streptomycin for gram negative organisms and caprylate sodium to targetyeast, all suspended in a silicone vehicle. Although, clinicalevaluation suggested that polyantibiotic paste conferred a therapeuticbenefit (fewer treatments to achieve a negative culture) the compositionwas ineffective against anaerobic species (which are now appreciated asthe dominant species responsible for treatment failure). In 1975 theFood and Drug Administration (FDA) banned PBSC for endodontic useprimarily because of the risks of sensitization and allergic reactionsattributed to the penicillin.

[0008] This underscores the importance of improving historicalendodontic methodologies, particularly local delivery methods, in lightof contemporary knowledge and technological advances.

SUMMARY OF THE INVENTION

[0009] The invention relates to endodontic fibers comprising abiocompatible polymer 20 vehicle which is permeable to medicaments, orcombinations of medicaments, dispersed, e.g., homogeneously, therein.Such fibers can be used, for example, in a method for the local deliveryand sustained release of medicaments to periodontal or intracanaltreatment sites. Endodontic fibers of this invention include modifiedperiodontal fibers and intracanal fibers.

[0010] One embodiment of the invention relates to modified periodontalfibers suitable for delivery of medicaments to intracanal treatmentsites. These first generation endodontic fibers, referred to herein as“modified peridontal fibers”, represent an adaptation of an ethylenevinyl acetate delivery vehicle (see U.S. Pat. Nos. 4,764,377 and4,892,736) previously developed to administer therapeutic agents duringthe course of periodontal treatment (Gilad, “Development of aClindamycin Impregnated EVA fiber as an Intracanal Medicament inEndodontic Therapy,” Master of Medical Sciences Thesis, HarvardUniversity School of Dental Medicine, defended Apr. 2, 1998, and Gilad,et al., “Development of a Clindamycin-Impregnated Fiber as an IntracanalMedication in Endodontic Therapy,” Journal of Endodontics,25(11):722-727 (1999), the entire teachings of which are incorporatedherein by reference). Specifically, the periodontal fibers have beenmodified to confer properties which allow the use of the fiber within anintracanal treatment site, e.g., to confer specific physicalcharacteristics such as form and consistency. In one embodiment, themodification comprises the treatment of the periodontal fiber with anagent such as a biocompatible refrigerant spray (e.g., Endo Ice).

[0011] In an alternative embodiment, the invention also relates to asecond generation endodontic fiber, referred to herein as an “intracanalfiber,” which can be specifically designed for use in intracanaldelivery methods, thereby obviating the need to modify a peridontalfiber for use in intracanal sites. Such design can include an alterationin the composition and/or ratio of components of the fiber. For example,as described herein, it has been discovered that an ethylene vinylacetate (EVA) fiber containing less than about 20% vinyl acetate issuitable for use as an intracanal fiber. In a preferred embodiment, theEVA fiber contains less than about 20%, preferably less than about 15%and more preferably less than about 10% vinyl acetate. In oneembodiment, the EVA fiber contains about 9.3% vinyl acetate. In apreferred embodiment, the intracanal fiber has a diameter of less thanabout 0.5 mm. In one embodiment the intracanal fiber has a diameter ofabout 0.3 mm.

[0012] The invention is demonstrated herein using clindamycin/ethylenevinyl acetate (EVA) fibers; however, this example is not intended tolimit the scope of the invention in any way. For example, thecontemplated intracanal fiber can be formulated to have a polymericcomposition, surface tackiness, stifffiess, glass transitiontemperature, and/or diameter selected to confer characteristicscompatible with placement within the root canal. Although the secondgeneration intracanal fiber is particularly adapted for intracanal use,other (i.e., non-intracanal) uses of this fiber are also envisioned. Forexample, the intracanal fiber can also be used for periodontaltreatment.

[0013] In addition, the choice of medicament and the dose at which it isincorporated 5 into the disclosed endodontic fibers (e.g., modifiedperidontal fibers or intracanal fibers) are optimized to produce a fiberthat is most likely to achieve the desired therapeutic effect. Theintracanal fibers exemplified and contemplated herein are ideally suitedfor the local delivery and sustained release of intracanal medicamentsand thus enable numerous intracanal delivery methods.

[0014] In one aspect of endodontic use, endodontic fibers (e.g.,modified peridontal fibers or intracanal fibers) are utilized for theintracanal delivery and sustained release of antibiotics predicted to beefficacious for the treatment of an established endodontic bacterialinfection. The goal of the intracanal delivery of antibiotics in thiscontext is to achieve a sufficient drug concentration and duration ofcontact, to effect inhibition (e.g., partial or complete inhibition) ofall bacterial growth within the pulp chamber and root canal, therebyobviating the need for systemic antibiotic administration. Ultimately,the ability to successfully treat established bacterial infections willreduce endodontic treatment failures.

[0015] In an alternative embodiment, an intracanal delivery method usingendodontic fibers of the invention is utilized prophylactically todisinfect a root canal receiving endodontic treatment prior to theapplication of a final restoration. In this context, the local deliverymethod is employed to eradicate any residual bacteria which were notremoved by the chemomechanical preparation of the canal. Morespecifically, the purpose of this method of delivery is to suppressbacterial growth, particularly the proliferation of black-pigmented,gram negative organisms within the root canal. Such prophylaxis canreduce the level of patient pain due to inflammation and the occurrenceof interappointment flare-ups, and ultimately minimize the risk oftreatment failures.

[0016] In other embodiments of the invention, endodontic fibersdescribed herein can be used to deliver alternative intracanalmedicaments necessitated by a course of endodontic treatment. Forexample, in an effort to attenuate a host-mediated inflammatory responseresulting from the presence of bacterial by-products in periapicaltissues, an anti-inflammatory agent, either alone or in combination withan antibiotic, can be incorporated into the endodontic fiber.

BRIEF DESCRIPTION OF THE FIGURES

[0017]FIG. 1 is a bar graph indicating the number of colony formingunits (CFUs) isolated from paper point or crushed teeth samples ofextracted human teeth infected in vitro with P. intermedia and treatedwith either periodontal clindamycin/EVA fibers, or EVA control fibers.

[0018]FIG. 2 are bar graphs indicating the CFUs isolated from extractedhuman teeth infected in vitro with a mixed inoculum of F. nucleatum, P.micros, and P. intermedia and treated with either periodontalclindamycin/EVA fibers or EVA control fibers. The graphs summarizeclindanycin activity against each of the three species of bacteriapresent in the inoculum.

[0019]FIG. 3 are bar graphs summarizing the CFU load recovered fromauto-infected ferret canine teeth undergoing root canal therapy, treatedwith either periodontal clindamycin/EVA fibers or EVA control fibers.

[0020]FIG. 4 is a graphic depiction of the kinetics of drug release fromintracanal fibers.

[0021]FIG. 5 is a graphic depiction of the kinetics of drug release fromintracanal fibers.

[0022]FIG. 6 is a graphic depiction of the kinetics of drug release fromcalcium hydroxide/gutta-percha points.

[0023]FIG. 7 is a graphic comparison of antibacterial activity ofintracanal fibers vs calcium hydroxide/gutta-percha points in extractedhuman teeth.

[0024]FIG. 8 is a graphic depiction of pre-treatment CFU versuspost-treatment CPU in extracted human teeth (paper point samples).

[0025]FIG. 9 is a graphic depiction of pre-treatment CPU versuspost-treatment CFU in extracted human teeth (crushed teeth samples).

[0026]FIG. 10 is a graphic depiction of the pre-treatment CFU versispost-treatment CPU in a ferret animal model (paper point samples).

DETAILED DESCRIPTION OF THE INVENTION

[0027] The role of endogenous microflora as a source of bacterialinfection contributing to endodontic treatment failure is wellestablished (Kakehashi, S. et al., Oral Surg., 20:340-348 (1965)). Thebacterial species most often associated with infections of endodonticorigin belong to the genera Prevotella, Porphyromonas, Fusobacterium,Peptostreptococcus, Eubacterium and Streptococcus. Some publishedstudies have implicated species of black-pigmented, gram negativeanaerobes as possible endopathogens (based on a frequency of isolationin the 25% to 50% range from teeth experiencing treatment failure),however, no single species has been proven to be more pathogenic thanothers (USAIDR Information Bulletin, 4(3) (1990)).

[0028] A “flare-up” is defined as pain and/or swelling which occurswithin a few hours to a few days after a root canal treatment procedure.Depending upon the severity of the symptoms, there is often a sufficientdisruption of the patient's lifestyle such that the patient initiates anunscheduled visit and treatment. Published studies suggest that thepresence of members of the black-pigmented Porphyromonas (particularlyPorphyromonas gingivalis and Porphyromonas endodontalis) within the rootcanal correlate with the type of acute symptoms responsible forinter-appointment flare-ups (Yoshida et al., J. Endodon., 13:24-28(1987)). Thus, in addition to reducing the failure rate of endodontictreatment, it also desirable to reduce the frequency of interappointmentflare-ups.

[0029] Antibiotics have historically been used as an adjunct toendodontic treatment, either by systemic or local administration.Currently, antibiotic treatment for root canal infections andexacerbations is limited to systemic administration. Commonly prescribedantibiotics include penicillins (e.g., penicillin V, amoxicillin),erythromycins (e.g., erythromycin stearate), lincosamides (e.g.,clindamycin) and cephalosporins (e.g., cephalexin). The decision to useantibiotics is often made by the practitioner in relation to his or herown treatment philosophy. The choice is made in light of the knowledgethat systemic antibiotics should be prescribed with restraint because ofthe possibilities of hypersensitivity or anaphylactic reactions,toxicity, adverse systemic effects, and the development of resistantstrains of microorganisms.

[0030] A critical reevaluation of the merits of delivery devices,vehicles, techniques, and medicaments which have been historicallyutilized for intracanal delivery methods reveals that the use ofintracanal medicaments in general, and in particular the use ofintracanal antibiotics, has been criticized for inadequate spectrum ofactivity and short duration of effectiveness. The former issue has beenaddressed by improved microbiological sampling techniques, particularlyanaerobic culturing techniques, which now provide practitioners with anaccurate profile of the bacterial species associated with endodonticinfections. This information enables practitioners to prescribe moreappropriate antimicrobial agents. As a result, the short duration ofeffectiveness emerged as the major flaw of intracanal deliveryprotocols. The endodontic fibers described herein address this issue byallowing a treatment strategy which is demonstrated to be capable of thesustained release of active medicament for at least 14 days (in vitro).

[0031] The disclosed endodontic fibers enable a delivery system andmethod capable of the sustained release of any class of medicament thatis necessitated as a consequence of therapy, particularly root canaltherapy. In preferred embodiments, the invention provides a therapeuticmethod for the treatment of an endodontic bacterial infection, oralternatively a controlled aseptic technique suitable for use as anadjunct to conventional chemomechanical debridement and irrigationtechniques.

[0032] Systemic administration relies upon circulatory elements to bringactive drug to an infected site. However, it is well recognized thatinfected and/or inflamed periradicular tissue and necrotic pulplessteeth do not posses a normal vasculature. This practical considerationrenders systemic administration inefficient, particularly when it iscombined with the knowledge that to be effective, an antibiotic must bein contact with the targeted microorganisms. These facts clearlycompromise the potential utility of systemically administeredprophylactic antibiotics.

[0033] In contrast, a local delivery strategy confers the therapeuticbenefit of delivering a medicament directly to the targeted tissuespace. In addition, use of the disclosed delivery vehicle and method isreadily amenable to both bacteriological sampling and sensitivityscreening in the event that an infection does not respond to an initialcourse of treatment, and the easy removal of the fiber in the case of anunforeseen complication or allergic reaction. The latter featurerepresents a significant improvement over the historical use of paste orliquid compositions.

[0034] Furthermore, the ability to establish substantial localconcentrations of an antibacterial agent also minimizes the risk ofcontributing to the development of drug resistant pathogens. One of themajor contraindications to the use of systemic antibiotics is thetheoretical possibility that bacteria not affected by the relatively lowconcentrations achieved by oral administration will give rise to strainshaving multiple drug resistance. Intracanal delivery also spares thepatient from unwanted side-effects commonly associated with systemicadministration strategies. For example, systemic clindamycinadministration has been associated with the occurrence ofpseudomembranous colitis, a sufficiently deleterious side effect whichaccounts for the reluctance of many clinicians to prescribe clindamycin,despite its broad spectrum of activity. However, given the dosagesrequired to cause pseudomembranous colitis, along with the requirementfor gastrointestinal contact, it is unlikely that the intracanal use ofclindamycin/EVA endodontic fibers would trigger such an adverse sideeffect. This later benefit can be decisive in terms of prescribing aparticular medicament whose spectrum of activity may be well suited forthe task, but systemic administration carries a high risk of toxicity.

[0035] The intracanal fibers described herein are specifically designedfor use in intracanal delivery methods. The optimal composition of thefibers can be empirically determined to confer the physicalcharacteristics and polymeric composition required for intracanal use.The intracanal fibers can have a diameter of from about 0.1 mm to about2.0 mm. In a preferred embodiment, the endodontic fiber has a diameterof from about 0.1 to about 0.5 mm; this particular diameter rangefacilitates placement deep within the cleaned and reshaped root canal.Most preferably, the intracanal fiber has a diameter of about 0.3 mm.Intracanal fibers suitable for use in the disclosed invention canfurther comprise additional features characteristic of the modifiedperiodontal fibers exemplified herein. More specifically, particularlypreferred fibers are characterized by additional features such as beingodorless, being colorless, permitting deep penetration of the rootcanal, being suitable for use with a variety of therapeutic agents,being capable of the sustained release of at least one active agent(e.g., for at least a one week period of time (in vitro)), and notstaining tooth structure or interfering with standard bacterial culturetechniques.

[0036] The composition and glass transition temperature of the polymercan also be selected to confer surface characteristics and a level ofrigidity required to accomplish the aseptic placement of the fiberwithin the root canal, and to facilitate the subsequent conformity ofthe fiber to the contours of the root canal. Biocompatible vehiclesuseful for the formulation of the disclosed endodontic fibers arebiocompatible synthetic or natural copolymers, which may or may not bebiodegradable. For example, polymers such as collagen, cellulosicpolymers, glycolic acid polymers, methacrylate polymers, ethylene vinylacetate polymers, ethylene vinyl alcohol copolymers, polycaprolactone,polyurethanes and polylactides and combinations thereof are suitable foruse in this invention. The form (i.e., shape) of the polymer compositionis not critical as long as the form allows the composition to bepositioned within the root canal, preferably the positioning required isdeep within the tooth canal to enable the medicament act locally at thesite of deep bacterial infection. In a preferred embodiment the form ofthe polymer composition is a string or fiber. For example, polymersuseful for the preparation of second generation intracanal endodonticfiber according to the invention contemplated herein are described inU.S. Pat. Nos. 4,764,377 and 4,892,736.

[0037] It is recognized that in the preparation of an endodontic fiberfor use in an intracanal delivery method, certain inert substances maybe included to further modify the delivery characteristics, or to serveas carriers of the active agent, including solvents, suspending agents,surfactants, viscosity-controlling agents, and other pharmaceuticallyacceptable materials which may be desirable to solubilize or stabilizethe therapeutic agent (or agents) in the delivery vehicle, or to controlthe rate of permeation or the action of the agents after permeation.

[0038] According to the invention, the modified periodontal fiber orintracanal fiber is impregnated with one or more medicaments usingmethods known in the art. A wide variety of medicaments may be used inthe invention, either alone or in combination. Therapeutic agentssuitable for use in the invention include, but are not limited to:antibiotics such as clindamycin, tetracycline, neomycin, kanamycin,metranidazole or canamycin; antimicrobial agents such as iodine,sulfonamides, mercurials, bisbiguanidines, or phenolics;anti-inflammatory agents such as indomethacin or hydrocortisone; immunereagents such an immunoglobulins, or antigen binding fragments ofimmunoglobulins or immunomodulatory agents such as methotrexate.

[0039] In addition, it is recognized that in certain forms of therapy,combinations of these agents in the same delivery vehicle may beutilized in order to obtain an optimal effect. Thus, for example, anantibiotic and an anti-inflammatory agent may be combined in thepreparation of a single endodontic fiber, which could be used either asan adjunct or a substitute for traditional endodontic treatmentprotocols.

[0040] The choice of medicament, and the dose at which it isincorporated into the endodontic fiber, can be selected to producefibers that achieve the desired therapeutic effect, in light of aparticular set of factors. For example, the initial selection of anappropriate antibiotic, and the dose at which incorporated into theendodontic fiber, are empirical choices guided by knowledge of thebacterial species commonly associated with treatment failure, thecondition of the particular tooth receiving treatment, and the time spanbetween scheduled appointments. Properties desirable in an idealintracanal antibiotic or antimicrobial agent (or combination thereof)for use during root canal treatment are that the medicament begermicidal to all, or at least a portion of, organisms present at thetreatment site, rapidly effective, capable of deep penetration into thecanal system, effective in the presence of organic matter, noninjuriousto periapical tissues, chemically stable, odorless, tasteless, andinexpensive. In practice, the selection of a therapeutic agent for usein the described intracanal delivery methods will be dictated by thepermeability of the delivery vehicle to the agent, the dose at which theagent can be incorporated into the fiber, and the toxicity of the agent.

[0041] For example, clindamycin is effective against many of thebacterial taxa commonly associated with endodontic treatment, anddepending on the effective concentration achieved at the site ofinfection it can be either a bacteriostatic or a bacteriocidalantibiotic. It is effective against: Actinomyces, Eubacterium,Fusobacterium, Propionibacterium, microareophilic Streptococci,Peptococcus, Peptostreptococcus, Veillonella, Prevotella, andPorphyromona. Also, hypersensitivity and anaphylaxis as a result ofclindamycin exposure is extremely rare. In addition, data presentedherein demonstrates that clindamycin/EVA intracanal fibers are active invitro against the black-pigmented Prevotella and Porphyromonas species,which are commonly associated with the occurrence of flare-ups.Clindamycin binds exclusively to the 50S subunit of bacterial ribosomesand interferes with peptidyl transfer, which prevents elongation ofpeptide chains and ultimately suppresses bacterial protein synthesis.(AHFS Drug Information Reference, 388-393 (1997)). The minimuminhibitory concentration (MIC) of clindamycin for most susceptibleaerobic and micoroaerophilic bacteria is 0.1-0.4 mg/mL, and is oftenobserved to be much lower than the corresponding penicillin orerythromoycin MIC. Published studies indicate that over the twenty yearperiod ending in 1986, there has been no marked change in thesensitivity of bacteria to lincomycins, and more specifically that 70%to 80% of all bacterial species isolated have remained susceptible toclindamycin. Conversely, a reduction in bacterial sensitivity,, and insome instances evidence of resistance, has emerged among amoxicillin,cephalosporins, and erythromycin during the same period of time (Woods,Aust. Dent. J., 33:420-423, 505-510 (1988)).

[0042] The use of the disclosed endodontic fibers and methods during thecourse of endodontic treatment can readily be adapted to complement atypical endodontic treatment program. Conventional root canal therapy isperformed over a series of visits, to allow sufficient time to pass fromthe initial pulpectomy, chemomechanical debridement, and irrigation toensure that the pulp chamber and root canal are aseptic prior to theapplication of the final restoration. Therefore, the anticipated use ofthe medicament-impregnated fiber in the context of either a prophylacticmethod, or for the treatment of an established infection, does notrequire, but could optionally utilize, a biodegradable polymer. Thecontrolled release characteristic of the fiber, combined with theopportunity for periodic replacement, makes the method compatible withconventional endodontic treatment protocols, and increases thelikelihood that the local administration will achieve its desiredtherapeutic effect.

[0043] The modified periodontal fiber and intracanal fiber claimed anddescribed herein are suitable for use in any and all of the disclosedmethods of intracanal delivery, including, but not limited to,prophylactic disinfection of the root canal, treatment of a bacterialinfection, attenuation of a host-mediated inflammatory response, and thesustained delivery of an appropriate intracanal medicament necessitatedby endodontic treatment.

[0044] The invention will now be further described by the followingnon-limiting 20 examples. The teachings of all literature, patents andpublished patent application referred to herein are incorporated hereinin their entirety.

EXAMPLES

[0045] Periodontal Fibers

[0046] Preparation of a Periodontal Clindamycin/EVA Endodontic Fiber andin vitro Efficacy Against Endodontic Pathogens

[0047] First generation (periodontal) clindamycin/EVA endodontic fiberswere prepared according to a method used for the preparation ofperiodontal tetracycline/EVA fibers (as described in U.S. Pat. No.4,892,736) with slight modifications. In brief, 0.075 g calciumphosphate monobasic (CaH₂PO₄) was combined with 10 mL distilled water(dH₂0) and added to a solution consisting of 0.050 g clindamycinphosphate and 10 mL dH₂0. The combined solution was then lyophilized for24 hours. The resultant powder was filtered through a #325 mesh sieve(W.S. Tyler Co., Mentor, Ohio) in order to achieve uniform particle sizeof 45μ. The resultant yield (125 mg) was combined with 375 mg of EVAparticles (USi Inc., TN) and processed through an extrusion plastometer(Tinius Olsen Co., Willow Grove, Pa.) at diameters of 2.0 mm, 1.0 mm,and 0.5 mm. The final extrusion produced a 250 mm long fiber, with acalculated approximate dose of 2.0 mg clindamycin/10 mm fiber.

[0048] Bacterial sensitivity to the modified peridontal clindamycin/EVAfiber was determined by placing 10 mm long fiber segments of on bloodagar plates colonized by the following bacterial species: F. nucleatum(ATCC 364), P. intermedia (ATCC 25621), P. micros (ATCC JH20), S.intermedius (ATCC 27335), P. endodontalis (ATCC 35406), P. gingivalis(ATCC 381), P. melaninogenica (ATCC 25845), E. lentum (ATCC 25559), V.parvula (ATCC 10790), S. sanguis (ATCC 551), P. buccae (ATCC 33574), P.oralis (ATCC 33269), or P. acnes (ATCC 11827). Assay plates wereincubated in anaerobic chambers for four days prior to the measurementusing a millimeter ruler and recording of the resulting zones ofinhibition. Table 1 summarizes the observed zones of inhibition. Controlfibers, consisting of EVA fibers without clindamycin, failed to produceany detectable growth inhibition of the above-listed bacterial species.These data demonstrate that periodontal clindamycin/EVA fibers havesignificant antimicrobial activity against endodontic microorganisms.

[0049] Table 1

[0050] Assessment of Periodontic Fiber Effectiveness Versus EndodonticBacteria in Vitro In vitro Suppression of Bacterial Growth in ExtractedHuman Teeth Infected with Endodontic Pathogens by PeriodontalClindamycin/EVA Fibers

[0051] To test the efficacy of the periodontal clindamycin/EVA fibers anin vitro assay was developed based on the use of extracted human teethwhich are persistently infected with endodontic pathogens. Thirty-twoextracted human teeth (anteriors/premolars) were sectioned at thecementoenamel junction, shaped with 0.04 taper nickel-titanium rotaryendodontic instruments (Tulsa Dental, Tulsa, Okla.) and fully cleanedwith 5.25% sodium hypochlorite (NaOCI), followed by thorough flushingwith distilled water. The smear layer was not removed. The teeth werethen sterilized by autoclaving for 20 minutes and coated with stickywax, leaving the apical foramen and coronal orifice patent.

[0052] In initial studies P. intermedia was grown on blood agar platesand was used as the infecting microorganism. BBL Mycoplasma broth wasprepared by sterilizing a solution consisting of 1.05 g of BBLmycoplasma broth powder with 0.1 g glucose, 0.5 15 g hemin, 50 mL dH₂0and 0.025 g L-cysteine (at pH 7.4-7.6). Under nitrogen influx, tubes ofsterile broth were combined with P. intermedia colonies from the stockagar plates, and diluted to a concentration of 10⁹ bacteria/mL (opticaldensity reading of 1.0@600 nm), and then diluted to 10⁶ bacteria/mL byadding 50 μL of bacterial broth to 450 μL sterile media. The sterileteeth were then introduced into tissue culture wells filled with thebacterial broth. The wells were lightly covered and placed in ananaerobic chamber for four days.

[0053] For sampling purposes, the teeth were moved into dry wells, andsterile paper points were inserted for 15 seconds. The resulting samplewas then dispersed by vortexing to release the sample microorganismsinto 1 mL aliquots of sterile media. 25 Ten-fold serial dilutions wereperformed by transferring 50 μL of bacterial broth into 450 μL ofsterile media under nitrogen influx for 10⁻², 10⁻³ and 10⁻⁴concentrations. 100 μL samples were spread onto blood agar plates, andcultured for four days under anaerobic conditions. On the fifth day theteeth were transferred into a second plate containing 500 μL of freshmedia and returned to anaerobic culture conditions for an additional 4days. After eight days, paper point sample plates corresponding to teethexhibiting positive growth were quantified for number of colony formingunits (CFUs) and two teeth had to be eliminated from the study due tolack of bacterial colonization. Seven colonized teeth were randomlyselected for use as control teeth (receiving 10 mm long EVA fibersformulated without any antibiotic), and seven other infected teeth wereutilized as experimental teeth (receiving 10 mm long periodontalclindamycin/EVA fibers). Periodontal clindamycin/EVA fibers wereprepared as described above, and to facilitate fiber manipulation andinsertion they were treated to decrease their surface tackiness andincrease their rigidity by spraying with a biocompatible refrigerantspray (such as Endo Ice) thereby producing “modified periodontalfibers.”

[0054] Following fiber placement the teeth were placed into new wellswith 500 μL of fresh sterile media and returned to anaerobic cultureconditions. Wells were replenished with fresh media daily for four days,at which point the teeth were sampled with paper points and assayed forbacterial colonization according to the serial dilution and platingmethod described above. To ensure the detection of bacterial speciescolonizing locations which are theoretically not accessible paper pointsampling (such as complex anatomical spaces in the root canal system, ordentinal tubules) entire teeth were individually fractured and crushedin sterile autoclave bags and then dispersed into culture tubescontaining 1 mL sterile media. Crushed-tooth samples were seriallydiluted and plated according to the method described above for the paperpoint samples. CPUs from the suitably diluted blood agar plates werequantified 7 days later. Colony identification was verified bymorphometric analysis. Statistical analysis of the differences observedbetween control (EVA fibers without antibiotic) and experimental(periodontal clindamycin/EVA fibers) were evaluated with thenon-parametic Wilcoxin Rank Sum Test.

[0055] The data in FIG. 1 demonstrate that periodontal clindamycin/EVAfibers are efficacious in suppressing bacterial growth in teeth infectedwith P. intermedia. All seven experimental teeth treated withperiodontal clindamycin fibers demonstrated no growth from either paperpoint or crushed tooth samples, demonstrating the efficacy of the fiber.In contrast, six of seven control teeth that received EVA fibersdemonstrated positive growth. Statistical analysis utilizing theWilcoxin rank sum test revealed no differences between baseline infectedteeth with respect to CPU quantification prior to fiber placement(p>0.05). Samples from both paper point and crushed experimental teethtreated with periodontal clindamycin/EVA were significantly differentfrom control teeth (p<0.05).

[0056] In a second experiment, the ability of periodontalclindamycin/EVA fibers to reduce bacterial infection with a mixedinoculum was assessed. Sixteen new teeth were prepared as describedabove, and placed into tissue culture wells containing 350 μL sterilemedia, and a mixture of 50 μL F. nucleatum, 50 μL P. micros and 50 μL P.intermedia at a concentration of 10⁹ bacteria/mL. Paper point sampleswere once again taken after four days to confirm and quantify bacterialgrowth. Modified peridontal fibers, prepared according to the methoddescribed above, were placed in 16 teeth for four days (eight controlsand eight experimental), and the teeth were transferred into wells offresh media daily. After obtaining paper point samples the teeth werecrushed and serially diluted samples were prepared, and plated asdescribed above.

[0057] One week following fiber placement, the CFU load was quantifiedand compared with baseline CPU counts. Colony identification was againverified by morphometric analysis. Wilcoxian rank sum tests revealedthat the differences between control and experimental teeth were allstatistically significant (p<0.05). When comparing individual teeth forpre-treatment and post-treatment CFU values by t-Test, F. nucleatumgroups were significantly different (p<0.05) as were P. intermediagroups (p:<0.05). However, the differences between the P. micros controland experimental groups were not significant (p>0.05). Thus, as shown inFIG. 2, the intracanal delivery of clindamycin was most effectiveagainst P. intermedia, less effective against F. nucleatum, andapparently ineffective against P. micros in the context of a mixedinoculum, despite the fact that clindamycin inhibits the growth of purecultures of P. micros on blood agar plates.

[0058] In vivo Suppression ofBacterial Growth in Auto-Infected RootCanals of Ferret Canine Teeth by Periodontal Clindamycin/EVA Fibers

[0059] Ferret canine teeth have been utilized successfiilly inendodontic research to study the induction of periapical lesions (Fouad,Endo. and Dent Trauma, 8:56-62 (1992)). The canine teeth are long andlarge enough to accommodate periodontal endodontic fiber placement, andtherefore, can provide an in vivo model system to evaluate the abilityof periodontal clindamycin endodontic fibers to inhibit bacterial growthin auto-infected root canals. Briefly, eight male ferrets (12 weeks old,approximately 3 lbs. each, Marshall Farms, Rose, N.Y.) were utilized toevaluate the in vivo efficacy of periodontal clindamycin/EVA fibers.Ferrets were premedicated with atropine (0.04 mg/kg, subcutaneously) 30minutes prior to the procedure. Animals were then anesthetizedintramuscularly with ketamine HCl (30 mg/kg) and xylazine (3 mg/kg) insterile PBS. This anesthetic treatment was supplemented with a repeatdose of ketamine and xylazine when necessary. The pulp cavity of thirtytwo ferret canine teeth (4 teeth per each of 8 animals) was surgicallyexposed (using a #2 round bur and a high speed handpiece). Workinglengths were confirmed radiographically. The root canal system wasinstrumented with 0.04 taper nickel-titanium rotary endodonticinstruments to approximately a 0.30 mm apical preparation and irrigatedwith sterile saline. The teeth were left open for seven days to allowfor bacterial colonization from the oral cavity. The auto-colonizedteeth were subsequently closed with a cotton pellet and IntermediateRestorative Material (IRM) for a period of 14 days to allow foranaerobic bacterial growth and the development of pathogenesis. Theteeth were then reopened (under general anesthesia) for modifiedperidontal fiber placement. Four of the eight animals receivedexperimental periodontal clindamycin/EVA fibers (four teeth/animal) andthe remaining four animals received negative control/EVA fibers. Theteeth were resealed with cotton and IRM.

[0060] Treatment efficacy was determined seven days later afterpreparing crushed tooth samples from the treated animals. Briefly, theanimals were placed under anesthesia, their mouths were swabbed withiodine and alcohol, the teeth were extracted intact and surfacesterilized with iodine and alcohol, before being crushed inside ofsterile autoclave bags. The fibers were subsequently removed, and thetooth fragments were placed into 1 mL of prereducedanaerobically-sterilized (PRAS) transport medium under nitrogen influx,and immediately transported to the laboratory for serial dilution andplating under nitrogen influx as described in the in vitro studiesabove. Although the ferret canine teeth were generally long enough toaccept and accommodate the fibers, they were sufficiently curved tocomplicate the extraction process. As a result some of the teeth werefractured and had to be excluded from the study.

[0061] Samples were serially diluted and incubated on blood agar platesin an anaerobic environment for seven days, and CFUs were quantified.Resultant data are presented in A, of FIG. 3. The average CFU countobserved for control teeth (EVA fibers only) is 5.19×10⁵ CPUs comparedto an average of 1.89×10⁵ CPUs for the experimental teeth (periodontalclindamycin/EVA fibers). This represented a 2.75-fold decrease in CPUload in the clindamycin treated teeth. The Wilcoxin rank sum testconfirmed that the differences between control and experimental groupswere statistically significant (p<0.05).

[0062] In a second experiment, two ferrets (one control and oneexperimental animal) were utilized. The control animal had four teethtreated with modified peridontal EVA fibers containing no clindamycinand a fifth tooth, neither accessed nor instrumented, but ultimatelyextracted, crushed, and sampled. The experimental animal had three teethreceiving modified peridontal clindamycin/EVA fibers and a fourth toothtreated with a modified peridontal tetracycline/EVA fiber. Paper pointand crushed tooth samples were prepared as described above; however, twoteeth were fractured upon extraction, and were not included in the dataset.

[0063] The resultant data are summarized in B, of FIG. 3. Due to thesmall sample, statistical analysis was not employed. Nonetheless, theexperimental teeth showed a 6.3-fold decrease in CPU load whenquantified from paper point samples, and a 4.3-fold decrease fromcrushed samples when compared with controls. The periodontaltetracycline/EVA fiber appeared to possess similar efficacy to that ofthe clindamycin fiber. The unaccessed control tooth showed no bacterialgrowth, establishing that the tooth isolation technique did not resultin any contamination from the external root surface.

[0064] DNA-DNA hybridization checkerboard analysis as described bySocransky et al., Biotechniques, 17:788-792 (1994), was performed, usingsamples harvested from blood agar plates following one week of growthfrom both of the above in vivo experiments. The proportion of teethcolonized with each bacterial taxa was evaluated (presence vs. absence).Summary data compares control (EVA fiber only) versus experimental(periodontal clindamycin/EVA- or periodontal tetracline/EVA-treated)teeth. The data indicate that the treatment of teeth with periodontalclindamycin/EVA fibers does not favor the development of a uniquebacterial profile relative to the profile observed in control teethreceiving control fibers.

[0065] Intracanal Endodontic Fibers

[0066] Preparation of an Intracanal Clindamycin/EVA Endodontic Fiber

[0067] Clindamycin fibers were manufactured in a manner similar to thatof the prototype Clindamycin/EVA fiber (Gilad, 1998). To improve itsphysical properties, different preparations of Ethylene Vinyl AcetateEVA (ELVAX®, DuPont, Wilimington, Del.) were combined (containing 18,25,28 and 30% vinyl acetate) and processed through an extrusionplastometer (Tinius Olsen Co., Willow Grove, Pa.).

[0068] Most of the vinyl acetate concentrations produced a sticky softfiber, lacking rigidity. ELVAX® grade 750 was chosen as the deliveryvehicle because of its similar rigidity to gutta-percha and the lack oftackiness of the former prototype. The grade 750 contains a lowpercentage of vinyl acetate (9.3%). The decrease of vinyl acetate in anEVA preparation increases its stiffness. The new, smaller (0.3 mm)diameter was achieved by a custom laser-calibrated orifice to fit theextrusion plastometer. In brief, 50 mg of clindamycin phosphate powder(Sigma Chemical Co., St. Louis, Mo.) was filtered through a #325 meshsieve (W.S. Tyler Co., Mentor, Ohio) to achieve uniform particle size of45μ. The resultant particles were combined with 150 mg of EVA pellets,grade 750 (ELVAX®, DuPont, Wilmington, Del.) and were sequentiallyprocessed through modified extrusion plastometer at 140° C. yieldingfibers with diameters of 2.0 mm, 1.0 mm, 0.5 mm, and finally 0.3 mm. Thefinal extrusion produced a 325 mm long fiber, which was cut at 13 mmsegments, containing an approximate dose of 2.0 mg clindamycin. Theseresultant intracanal fibers have the following improvements overperiodontal fibers: increase in rigidity similar to traditionalgutta-percha points, thus eliminating the need of a refrigerant sprayprior to canal insertion, reduction in diameter from 0.5 mm to 0.3 mm,and maintenance of a 2.0 mg dose despite a reduction in diameter. Thereduction in diameter allows the penetration of the fiber deeper intothe root canal, possibly releasing antibiotic closer to the apex apicalaccessory canals.

[0069] Spectrophotometric Analysis of intracanal Clindamycin/EVA and Ca(OH) J Guttapercha Release

[0070] Clindamycin release from intracanal fibers was determinedspectrophotometrically (1 mg/mL clindamycin equal to an optical densityreading of 1.0@218 nm). Pour fibers were placed individually in sterileEppendorf tubes containing 1 mL of PBS at 36° C. to determine antibiotickinetic release. Samples were obtained after one hour and transferredwith sterile cotton pliers to a new tube containing 1 mL PBS at thefollowing time intervals: 2, 4, 6, 12 hours; 1, 2, 3, 4, 5, 6, 7, 14 and21 days (as shown in FIG. 4). The results showed an initial mean releaseof 132.5 μg/mL at 1 hour, a maximum mean release of 175.5 μg/mL at 48hours, and a gradual decrease to a mean release of 2.5 μg/mL at 21 days.The total amount of clindamycin released under these conditions to day21 was 1249 μg/mL, about 61% of the total drug in the fiber.

[0071] In another experiment, two intracanal clindamycin/EVA fibers weresimilarly assessed after 1, 2, 3, 4, 5, 6, 7, 14 and 21 days. Theclindamycin content of samples was determined spectrophotometricallywith reference to the standard. Clindamycin release characteristics ofCa(OH)₂/Gutta-percha points (Roeko, Langenau, Germany) were alsodetermined. Ca(OH)₂/Gutta-percha points (ISO #25) measuring 13 mm fromthe tip were analyzed spectrophotometrically at the following timeintervals: 1, 2, 3, 4, 5, 6, 7, 14 and 21 days at 36° C. (1 mg/mL in PBSequals optical density reading of 1.0@719 nm. The results (FIG. 5)showed an initial maximum mean release of 189.5 μg/mL at 1 day,gradually decreasing to 62 μg/mL at day 5 and subsequently declining to9 μg/mL at day 14. Interestingly, on day 21, there was a slight increaseobserved to 26 μg/mL. The total release of clindamycin between day 1 andday 21 was 717.5 μg/mL, about 36% of the total amount of drug in thefibers.

[0072] These results suggest that clindamycin release decreases when theconcentration of the drug in the external environment is high, andincreases when the concentration is low.

[0073] The release characteristics of Ca(OH)₂/gutta-percha points wereanalyzed at 1, 2, 3, 4, 5, 6, 7, 14 and 21 days. As shown in FIG. 6, theinitial mean release was 16.5 μg/mL on day 1 and a maximum mean releaseat day 2 and 3 (27.75 and 25.75 μg/mL respectively), a decrease to 4μg/mL at 5 days and a gradual increase to 30.25 μg/mL at day 21. Thetotal mean release between day one and day 21 was 162.5 μg/mL

[0074] Determination of Bacterial Sensitivity

[0075] The bacterial sensitivity to the clindamycin fiber wasestablished by placing 13 mm×0.3 mm diameter fiber segments on bloodagar plates colonized by the following common endodontic microbes: F.nucleatum (ATCC 364), P. intermedia (ATCC 25621), P. micros (ATCC JH20),S. intermedius (ATCC 27335), P. gingivalis (ATCC 381), S. sanguis (ATCC551), P. acnes1 (ATCC 11828). The fibers were handled with sterilecotton pliers. Controls consisted of EVA fibers without clindamycin. Theplates were then placed into an anaerobic chamber after four days, andzones of inhibition were measured with a millimeter ruler and recorded.Similar evaluations were simultaneously conducted with a 13 mm (ISO #25)Ca (OH) 2/Gutta-percha point (Roeko, Langenau, Germany), a 13 mmpremixed paste extrusion of calcium hydroxide (Pulpdent, Brookline,Mass.), and a control 13 mm EVA fiber as a negative control. Theintracanal fibers produced varying degrees of inhibition. P. intermedia,p. gingivalis and F. Nucleatum demonstrated the greatest susceptibilityto the intracanal fibers; while S. sanguis and P. acnes demonstratedintermediate susceptibility. Conversely, control EVA fibers, Ca(OH)₂premixed paste (Pulpdent) and Ca(OH)₂ Gutta percha points did notgenerate any inhibition of any organism. These data demonstrate thatintracanal clindamycin/EVA fibers have significant antimicrobialactivity against most endodontic microorganisms. Table 2 summarizes thezone of inhibition.

[0076] Table 2

[0077] Zones of Inhibition of Bacterial Growth Induced by IntracanalMedic aments

[0078] In vitro Model to Evaluate Fiber Efficacy

[0079] To test the efficacy of clindamycin/EVA fibers in reducingbacterial growth in infected human root canals in vitro, a model wasdeveloped to persistently infect extracted human teeth with endodonticpathogens. Twenty-four extracted human teeth, (anteriors and premolars)were sectioned at the cementoenamel junction, fully instrumented andshaped with 0.06 taper nickel-titanium rotary endodontic instruments(Tulsa Dental, Tulsa, Okla.) at approximately 0.3 mm apical preparation,leaving the apical foramen and coronal oriface patent. Teeth wereirrigated with 5.25% sodium hypochlorite (Na)CL followed by thoroughflushing with distilled water. The smear layer was not removed. Theteeth were then sterilized by autoclaving for 25 minutes. The teeth weredivided into three groups of eight teeth each as follows: (1) Control(EVA alone); (2) calcium hydroxide gutta-percha point; and (3)intracanal clindaymycin/EVA fiber.

[0080] Under nitrogen influx, four flasks of sterile broth were eachcombined, with P. intermedia, P. micros, S. intermedius and F. nucleatumcolonies from approximately 3×8 mm longitudinal slices of the stock agarplates. Each flask contained 25 mL of sterile BBL mycoplasma broth. Thefour flasks were maintained in an anaerobic chamber and were transferreddaily to four flasks containing 100 mL, and 500 mL producing a total of625 mL of inoculated BBL Mycoplasma broth. At the end of the experiment,500 mL of the inoculated broth was centrifuged at 9000 rpm for 20minutes. The supemanants were removed and each of the four pellets werediluted to a concentration of 10⁹ bacteria/mL (optical density readingof 1.0@600 nm), and then diluted to 10⁸ bacteria/mL by combining theinoculated broth with sterile prereduced anaerobically sterilizedtransport medium (PRAS), all under nitrogen influx. The sterile teethwere then introduced into sterile tissue culture wells (Coming Inc.Coming, N.Y.) containing 600 μL of sterile broth, and a mixture of 100μL of F. nucleatum, 100 μL of P. micros, 100 μL of F. intermedia and 100μL of S. intermedius at a concentration of 10⁸. The teeth were coveredand placed in an anaerobic chamber for four days to allow for bacterialgrowth. Control fibers (EVA alone), calcium hydroxide/gutta-perchapoints or the intracanal clindamycin/EVA fibers were placed in eachgroup of teeth. The teeth were replaced into fresh wells with 500 μL ofsterile media, covered and incubated in the anaerobic chamber. The wellswere replenished with sterile media every day until the next sampling(four days). The paper point samples were dispersed and vortexed in 1 mLof sterile PRAS transport medium under nitrogen influx. Ten-fold serialdilutions were performed by transferring 100 μL into 900 μL of (PRAS)under nitrogen influx for 10⁻², 10⁻³ and 10⁻⁴ dilutions. Finally, 100 μLsamples were spread onto blood agar plates, and allowed to grow for fivedays under anaerobic conditions. The CPUs were quantified under lightmicroscopy using a grid. Pour days after the placement of the deliverysystems, the teeth were paper point sampled and assessed by serialdilution. To ensure that no bacterial were missed from complexanatomical spaces in the root canal system or from dentinal tubules, theteeth were individually fractured and crushed in sterile PRAS. Ten foldserial dilutions were performed as detailed above from the paper pointsamples and the crushed teeth samples. The CPUs from the diluted bloodagar plates were quantified 7 days later. Statistical Analysis wasdetermined between test groups in the in vitro model utilizing extractedhuman teeth using the ANOVA method and the Tukey's studentized rangetest. The ANOVA method revealed that there were no significantdifferences in infection levels at baseline prior to fiber placement(p=0.31134). However, after treatment both paper point and crushedexperimental teeth treated with intracanal fibers has a statisticallysignificant reduction in infection levels at 4 days post-treatment(p=0.0001) (FIGS. 7, 8, and 9) A statistically significant reduction wasalso noted for the Ca(OH)₂ gutta-percha group compared to the controlgroup, although this was not as profound as the reduction by theintracanal fibers (FIG. 7). The intracanal fibers had the largest meanreduction (1515.8 CFUs), which is statisticall'significant from theCa(OH)₂ gutta-percha group (701.6 CFUs) with (p<0.05). The Tukey'sstudentized range test also showed that the difference in post-treatmentCFUs between the intracanal fiber group and the Ca(OH)₂ gutta-perchagroup was not statistically significant.

[0081] In vivo Suppression ofBacterial Growth in Auto-Infected RootCanals of Ferret 25 Canine Teeth by Intracanal Clindamycin/EVA Fibers

[0082] A similar protocol to the periodontal in vivo study detailedabove was conducted. Briefly, teeth from six ferrets were utilized intofour treatment groups. The groups were control/EVA fibers,clindamycin/EVA intracanal fibers, Roeko® fibers and calcium hydroxidepaste.

[0083] The ferrets were infected with a mixture of four commonendodontic pathogens, including Streptococcus intermedius, Fusobacteriumnucleatim, Peptostreptococcus micros, and Prevotella intermedia.

[0084] To analyze the residual infection, paper point samples weretaken, the teeth were extracted and then crushed to release all bacteriawithin the root canals. The results are shown in FIG. 10.

[0085] While this invention has been particularly shown and describedwith reference to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. An endodontic fiber suitable for the localdelivery and sustained release of one or more medicaments incorporatedtherein to an intracanal treatment site, comprising a copolymer vehiclehaving incorporated therein one or more medicaments.
 2. The endodonticfiber of claim 1, wherein the medicament is selected form the groupconsisting of antibiotics, anti-inflammatory agents, antimicrobialagents, immune reagents, and immunomodulatory agents or a combinationthereof.
 3. The endodontic fiber of claim 2, wherein the medicament isan antibiotic selected from the group consisting of clindamycin,tetracyline and combinations thereof.
 4. The endodontic fiber of claim1, wherein the fiber is an ethylene vinyl acetate copolymer having adiameter of from about 0.1 mm to about 2.0 mm and the antibiotic isclindamycin incorporated at a dose of about 2.0 mg to about 5.0 mg mgper 10 mm of fiber.
 5. The endodontic fiber of claim 2, wherein themedicament comprises a combination of an antibiotic and ananti-inflammatory agent.
 6. A modified periodontal fiber suitable forthe delivery and sustained release of medicament incorporated therein toan intracanal treatment site, comprising a copolymer vehicle havingincorporated therein one or more medicaments, wherein the copolymer istreated to decrease its surface tackiness and increase its rigidity. 7.A method for the local delivery and sustained release of a medicament toan intracanal treatment site comprising: (a) obtaining an endodonticfiber suitable for intracanal use having one or more medicamentsincorporated therein; (b) positioning the fiber of (a) in the root canalsuch that the fiber is in direct contact with the treatment site; and(c) maintaining the fiber at the treatment site, wherein the medicamentis delivered to the treatment site at a controlled rate.
 8. The methodof claim 7, wherein the endodontic fiber is a modified periodontal fiberor an intracanal fiber.
 9. A method of treating an endodontic bacterialinfection comprising the steps of: (a) obtaining an endodontic fibersuitable for intracanal use having one or more medicaments incorporatedtherein; (b) inserting the fiber of (a) into the root canal such thatthe fiber is in direct contact with the treatment site; and (c)maintaining the fiber at the treatment site, wherein the antibiotic isdelivered to the treatment site.
 10. The method of claim 9, wherein theendodontic fiber is a modified periodontal fiber or an intracanal fiber.11. A method of disinfecting a root canal receiving endodontic treatmentcomprising: (a) obtaining an endodontic fiber suitable for intracanaluse having one or more medicaments incorporated therein; (b) insertingthe fiber of (a) into a debrided and irrigated root canal such that thefiber is in direct contact with the treatment site; and (c) maintainingthe fiber at the treatment site, wherein the medicament is administeredto the treatment site at a controlled rate.
 12. The method of claim 11,wherein the endodontic fiber is a modified periodontal fiber or anintracanal fiber.
 13. A method of reducing inflamation in periapicaltissue of a tooth undergoing endodontic treatment, comprising: (a)obtaining an endodontic fiber suitable for intracanal use havingincorporated therein an anti-inflammatory agent; (b) positioning thefiber into a debrided and irrigated root canal such that the fiber is indirect contact with the inflamed tissue; and (c) maintaining theendodontic fiber at the treatment site, wherein the anti-inflammatoryagent is delivered to the site of inflammation.
 14. The method of claim13, wherein the endodontic fiber is a modified periodontal fiber or anintracanal fiber.
 15. An intracanal fiber which is an ethylene vinylacetate copolymer comprising less than about 20% vinyl acetate.
 16. Anintracanal fiber according to claim 15, comprising less than about 15%vinyl acetate.
 17. An intracanal fiber according to claim 15, comprisingless than about 10% vinyl acetate.
 18. An intracanal fiber according toclaim 15, comprising about 9.3% vinyl acetate.
 19. An intracanal fiberaccording to claim 15, having a diameter of less than about 0.5 mm. 20.An intracanal fiber according to claim 18, having a diameter of lessthan about 0.5 mm and one or more medicament incorporated therein.